Toxicology Research Today is a free monthly online journal that collates and summarizes the latest research about Toxicology, including details on forensic toxicology, carcinogenicity, assays.

Is Mutatrade markMouse insensitive to clastogens?

Lynch AM, Mahabir AG, Bradford A, Brockhurst K, van Benthem J, van Steeg H, Rees RW

GlaxoSmithKline, Department of Genetic Toxicology, Ware, United Kingdom.

Several studies suggest that Mutatrade markMouse is insensitive to clastogens, including the accompanying paper by Mahabir et al., which describes a study with bleomycin, camptothecin, m-AMSA (4'-(9-acridinylamino)-methanesulfon-m-anisidide) and its ortho-analogue, o-AMSA (4'-(9-acridinylamino)-methanesulfon-o-anisidide). Only camptothecin was clastogenic in Mutatrade markMouse and none of these four compounds induced mutations at the lacZ locus. However, to improve exposure, dose range-finding studies were performed in CD2F1 mice, the parental strain of Mutatrade markMouse. Male CD2F1 mice (n=3) were treated with bleomycin (25-100mg/kg bw, p.o. and i.p.), camptothecin (1-10mg/kg bw p.o.) and m-AMSA (10-50mg/kg bw p.o. and 1-5mg/kg bw i.p.) for 5 days and blood was sampled on day 3 and/or day 6 for analysis by flow cytometry to determine % MN-RETs. Camptothecin (1mg/kg bw, day 6) induced a 3.6-fold increase in % MN-RET (P<0.05) but was toxic at higher doses. All day-3 camptothecin samples were positive (P<0.05). Bleomycin was negative when administered p.o. but positive at all doses on both days when given i.p. (P<0.05) whereas m-AMSA was negative when given i.p. or orally. Based on these results, male Mutatrade markMouse mice (5 per group) were dosed daily with bleomycin (50mg/kg bw) for 5 days or with camptothecin (5mg/kg bw) for 2 days. Peripheral blood was sampled 24h after the final dose in each group and tissues were sampled 37 days later. Both compounds induced significant increases in % MN-RET, but only bleomycin induced a significant increase in MF (6-fold in liver, 4.5-fold in kidney and 2-fold in lung) compared with the untreated control. These studies support the view that Mutatrade markMouse is insensitive to compounds where the genotoxic mechanism of action is predominantly clastogenesis, but demonstrates that the peripheral blood micronucleus test is a useful adjunct to the transgenic gene-mutation assay.

Published 2 May 2008 in Mutat Res, 652(2): 145-50.
Full-text of this article is available online (may require subscription).

© 2005-2008 Toxicology Research Today. All Rights Reserved.